Genome-wide association studies (GWAS) have identified many variants associated with cardiovascular-related diseases, some of which are novel. However, similar to other common diseases, these identified risk-associated variants fail to explain a significant portion of the genetic heritability of cardiovascular disease (CVD). Moreover, many associated variants are non-coding with no obvious function, though putatively, these are involved in gene regulation. By combining results of GWAS with expression quantitative trait locus (eQTL) mapping one can identify functional variants that influence gene expression and are also associated with disease risk. Using such combination of approaches one can identify true weak associations that are otherwise difficult to distinguish from statistica noise using a GWAS approach alone, as well as develop an immediate intuition regarding both the function of associated variants and knowledge of the implicated genes. However, for this method to be most effective, eQTL studies should be performed in cells that are relevant to the phenotype of interest, which are often not easily accessible in population samples. Indeed, nearly all eQTL mapping studies in humans to date (including the studies we performed in the first term of this grant) used gene expression measurements from blood cell types, fibroblasts, or lymphoblastoid cell lines (LCLs). In that sense, induced pluripotent stem cells (iPSCs) can change human genetics in a profound way. The ability to differentiate iPSCs can allow us to perform functional studies in the most relevant cell types. We thus propose to map eQTLs and investigate the genetic basis of cardiovascular disease in cardiomyocytes, which will be differentiated from induced pluripotent stem cells (iPSCs) of 120 Hutterite individuals. The Hutterites are a founder population of European descent that practices a communal, farming lifestyle. The Hutterites of South Dakota, the subjects of our studies, live on communal (15-25 families) farms (called colonies), where all meals are prepared and eaten in a communal kitchen, smoking is prohibited (and rare), and early life environments are extremely uniform. Our specific aims are to reprogram iPSCs from the LCLs of 120 Hutterites and obtain differentiated cardiomyocytes from each individual (aim 1), map eQTLs in differentiated cardiomyocytes (aim 2), and integrate eQTL mapping with GWAS results to identify variants associated with CVD-related phenotypes (aim 3). At the conclusion of this work we expect to gain important insight on the genetic basis of gene regulation in the heart in general, as well as on gene regulatory variation that is associated with CVD risk.